One persistent obstacle to treating HIV infection is the ability of virus to enter a latent state, inaccessible to current antiretroviral (ARV) therapy. How HIV enters latency and remains latent is only partially understood. One theory is that changes in chromatin structure, such as histone deacetylation, suppress transcription from the HIV long terminal repeat (LTR), resulting in the establishment of latency. IL-7, prostratin, and histone deacetylase inhibitors have been tested to purge HIV from the latently infected reservoir. However, no appreciable decrease of the latent reservoir is observed when these drugs are combined with ARVs. In contrast to reactivating latent provirus, a drug that blocks cellular activation might reduce the initial burst of viremia and limit establishment of the latent viral reservoir. Cyclosporin A (CSA), an immunosuppressive agent, has been shown to suppress viral replication and restore normal CD4 T-cell levels. However, adverse effects of CSA advocate against its use in HIV disease. Development of new approaches to purge the HIV reservoir and prevent establishment of latency are critical therapeutic challenges.